1. Field of the Invention
The present invention relates to a protein delivery system.
2. Description of the Related Art
Proper glycaemic control is crucial for diabetic patients to slow down disease progression and its long-term chronic complications. The need for life-long daily (or more) insulin injections (the standard treatment for type I and eventually for type II diabetics) decreases patient compliance, can be painful and runs the risk of local infections (Gonzalez et al., 2006; and Lassmann-Vague et al., 2006). Currently, the oral route is not feasible for insulin which, like most peptides and proteins, is prone to fast clearance and enzyme-catalyzed degradation by the harsh environments along the gastro-intestinal tract (GIT), resulting in <0.5% insulin bioavailability (Cefalu et al., 2004).
Insulin—native or chemically modified—formulated in a carrier that will withstand the harsh GIT conditions, has been tested. To gain the most from each administered dose, such a carrier should, furthermore, act through muco-adhesion as a slow-release insulin-depot within the GIT. Carrier types tested for the task include hydrogels, microspheres, nanoparticles, microemulsions and liposomes (Morishita et al., 2006).
Glycosaminoglycans, or mucopolysaccharides, along with collagen, are the chief structural elements of all connective tissues. Glycosaminoglycans, or gags, are large complexes of polysaccharide chains associated with a small amount of protein. These compounds have the ability to bind large amounts of water, thereby producing a gel-like matrix that forms the body's connective tissues. Gags are long chains composed of repeating disaccharide units (aminosugar-acidic sugar repeating units). The aminosugar is typically glucosamine or galactosamine. The aminosugar can also be sulfated. The acidic sugar may be D-glucuronic acid or L-iduronic acid. In vivo, gags other than hyaluronic acid are covalently bound to a protein, forming proteoglycan monomers. The polysaccharide chains are elongated by the sequential addition of acidic sugars and aminosugars.
Among the most common gags are hyaluronic acid, keratan sulfate, chondroitin sulfate, heparin sulfate, and dermatin sulfate. Gags may be chemically modified to contain more sulfur groups than in their initially extracted form. In addition, gags may be partially or completely synthesized and may be of either plant or animal origin.
Hyaluronic acid is a naturally occurring member of the glycosaminoglycan family which is present in particularly high concentration in the cartilage and synovial fluid of articular joints, as well as in vitreous humor, in blood vessel walls, and umbilical cord and other connective tissues. Hyaluronic acid can be in a free form, such as in synovial fluid, and in an attached form, such as an extracellular matrix component. This polysaccharide consists of alternating N-acetyl-D-glucosamine and D-glucuronic acid residues joined by alternating β-1,3-glucuronidic and β-1,4-glucosaminidic bonds. In water, hyaluronic acid dissolves to form a highly viscous fluid. The molecular weight of hyaluronic acid isolated from natural sources generally falls within the range of 5×104 up to 107 daltons. Hyaluronic acid has a high affinity for the extracellular matrix and to a variety of tumors, including those of the breast, brain, lung, skin, and other organs and tissues.
There are two basic classes of drug carriers: particulate systems, such as cells, microspheres, viral envelopes, and liposomes; and non-particulate systems, which are usually soluble systems, consisting of macromolecules such as proteins or synthetic polymers.
U.S. Pat. No. 5,733,892 to Sakurai et al. discloses lipidated glycosaminoglycan molecules which are soluble in aqueous solution (i.e., not insoluble particles). WO 03/015755 discloses a similar system but of lipidated glycosaminoglycan particles which form suspensions of insoluble particles in an aqueous phase. WO 2006/050246 discloses an improvement of the lipidated glycosaminoglycan particles of WO 03/015755 to provide a satisfactory solution to the problems associated with targeted delivery of water insoluble and poorly water soluble drugs such as paclitaxel (taxol).
Citation of any document herein is not intended as an admission that such document is pertinent prior art, or considered material to the patentability of any claim of the present application. Any statement as to content or a date of any document is based on the information available to applicant at the time of filing and does not constitute an admission as to the correctness of such a statement.